We describe in this paper that the diterpenes 8,10,18-trihydroxy-2,6-dolabelladiene ( 1) and (6 R)-6-hydroxydichotoma-4,14-diene-1,17-dial ( 2), isolated from the marine algae DICTYOTA PFAFFII and D. MENSTRUALIS, respectively, inhibited HSV-1 infection in Vero cells. We initially observed that compounds 1 and 2 inhibited HSV-1 replication in a dose-dependent manner, resulting in EC (50) values of 5.10 and 5.90 microM, respectively, for a multiplicity of infection (MOI) of 5. Moreover, the concentration required to inhibit HSV-1 replication was not cytotoxic, resulting in good selective index (SI) values. Next, we found that compound 1 sustained its anti-herpetic activity even when added to HSV-1-infected cells at 6 h after infection, while compound 2 sustained its activity for up to 3 h after infection, suggesting that these compounds inhibit initial events during HSV-1 replication. We also observed that both compounds were incapable of impairing HSV-1 adsorption and penetration. In addition, the tested molecules could decrease the contents of some HSV-1 early proteins, such as UL-8, RL-1, UL-12, UL-30 and UL-9. Our results suggest that the structures of compounds 1 and 2, Brazilian brown algae diterpenes, might be promising for future antiviral design.

Diterpene metabolites produced by Dictyota species are known to inhibit feeding by several herbivorous species. We present the first evidence of feeding-deterrence of dictyotacean metabolites of an unusual compound belonging to a dichotomane diterpene skeleton type. Through experimental assay, we provide evidence of feeding-deterrent properties of lipid-soluble extracts of the Brazilian brown alga D. menstrualis (Hoyt) Schnetter, Hörnig & Weber-Peukert against the amphipod Parhyale hawaiensis Dana. Bioassay fractionation of this extract revealed the deterrent activity to be due to the diterpenoid (6R)-6-hydroxydichotoma-3,14-diene-1,17-dial, which was found to be the second most abundant metabolite (~0.2% dry mass) in D. menstrualis. In contrast to other studies, the major diterpenoid pachydictyol A, present as 0.4% (dry mass) in D. menstrualis, showed no anti-feeding properties. Our results suggest that chemical defense of Dictyota species may vary according to geographic region, thus explaining the presence of a metabolite other than pachydictyol A which functions as the anti-feedant metabolite in D. menstrualis from the Brazilian littoral zone.

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It has been recently demonstrated that HIV-1 reverse transcriptase is the target of two diterpenes, (6 R)-6-hydroxydichotoma-3,14-diene-1,17-dial (compound 1) and (6 R)-6-acetoxydichotoma-3,14-diene-1,17-dial (compound 2), that inhibit HIV-1 replication in vitro. In this work, the effects of both diterpenes on the kinetic properties of the recombinant HIV-1 reverse transcriptase (RT) enzyme were evaluated. RNA-dependent DNA-polymerase (RDDP) activity assays demonstrated that both diterpenes behave as non-competitive inhibitors with respect to dTTP and uncompetitive inhibitors with respect to poly(rA).oligo(dT) template primers. The K(i) values obtained for compounds 1 and 2 were 10 and 35 microM, respectively. Neither of these diterpenes affected the DNA-dependent DNA-polymerase (DDDP) activity of the HIV-1 RT. The RDDP activities of AMV-RT and MMLV-RT enzymes were also inhibited by compounds 1 and 2. In contrast to the HIV-1 enzyme, the DDDP activities of AMV-RT and MMLV-RT enzymes were significantly reduced by compound 1. Taken together, our results demonstrate that compound 1 is a more effective inhibitor of the viral reverse transcriptases from HIV-1, AMV and MMLV than compound 2. The kinetic behavior analyses of the HIV-1 RT demonstrate that both diterpenes have similar mechanisms of inhibition of RDDP activity.

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